Cisapride extended release

ABSTRACT

The present invention concerns extended release formulations comprising cisapride-(L)-tartrate, in particular an oral formulation, the use thereof as a medicine, especially in treating gastrokinetic disorders.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of Ser. No. 08/817,739,filed Apr. 23, 1997. Now U.S. Pat. No. 6,153,623, which application isthe national stage and continuation of application Ser. No.PCT/EP95/04198, filed on Oct. 25, 1995, which application claimspriority from EP 94.203.184.0, filed on Nov. 2, 1994.

The present invention concerns extended release formulations comprisingcisapride-(L)-tartate, in particular for oral administration, the usethereof as a medicine, especially in treating gastrointestinaldisorders.

European Patent No. 0,076,530 discloses the gastroprokinetic agentcisapride and classic compositions thereof. Cisapride has the followingstructural formula:

The systematic chemical name of cisapride iscis-4-amino-5-chloro-N-[1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide.Cisapride is a racemic mixture of two enantiomers. Cisapride hasexcellent gastrointestinal motility stimulating properties and isreported to be devoid of antidopaminergic activity. Its utility in avariety of gastrointestinal disorders has already been reportedextensively.

Useful extended release formulations of cisapride for oraladministration should release the active ingredient, i.e. cisapride,over a long period of 15 to 24 hours, that is through the wholegastro-intestinal tract with its varying pH values. However, thesolubility of cisapride depends very much on the surrounding pH. Thesolubility of cisapride is the highest in a strongly acidic medium at pH1 to 2, such as for example in gastric juice. The solubility diminishesrapidly when the pH of the (physiological) medium increases, for examplein the intestines. An effective sustained release formulation ofcisapride should therefore function not only in highly acidic but alsoin less acidic or neutral media Moreover an extended release formulationshould release the active ingredient as soon as the formulation isadministered and should release the active ingredient in a constantmanner, preferably following zero order to first order kinetics. Thisprofile is desired because it provides relief to the patient very soonafter administration and overdosing is avoided when administering theformulation for a consecutive time.

A solution to this problem was found in the use of(+)-cis-4-amino-5-chloro-N-[1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide[R(R*,R*)]-2,3-dihydroxybutanedioate (1:1)—referred to hereinunder as“cisapride-(L)-tartrate”—in a matrix formulation as describedhereinafter. Cisapride-(L)-tartrate is the salt of racemic cisapridewith (+)-L-tartaric acid and is exemplified in European Patent No.0,076,530 as compound number 241.

An additional aspect of this invention is the fact that the productionprocess for the present extended release formulations is very simple asis shown in the examples hereinunder. This is in contrast to theproduction processes known in the art for preparing extended releaseformulations.

In comparison with other salts of cisapride the salt form with[R(R*,R*)]-2,3-dihydroxybutanedioic acid, i e. (+)-L-tartaric acid (thenatural form of tartaric acid) shows a remarkably good solubility inwater. Cisapride being a racemic mixture and L-tartaric acid being onesingle enantiomer, the resulting salt form is in principle a mixture oftwo diastereomeric salts: (+)-cisapride-(L)-tartate and(−)-cisapride-(L)-tartrate.

Unexpectedly, it was shown that the salt cisapride-(L)-tartrate is amixture of the diastereomers [(3R4S)(2R3R)] and [(3S4R)(2R3R)], thatcrystallize as a double salt in a 1:1 ratio. (This is confirmed byX-ray.) The (3R4S) and (3S4R) refer to the respective enantiomers ofcisapride and the (2R3R) refers to the optically pure L-tartrate.

Unexpectedly, it was found that formulations containingcisapride-(L)-tartrate released cisapride in a racemic form, i.e. equalamounts of (+)-cisapride and (−)-cisapride or in other words thediastereomeric salt forms (+)-cisapride-(L)-tartrate and(−)-cisapride-(L)-tartrate unexpectedly have equal dissolution rates.

Moreover, it was also found that during the preparation ofcisapride-(L)-tartrate no enrichment of one of the two diastereomericsalt forms could be detected.

Compositions according to the present invention comprisepharmaceutically acceptable carriers and excipients, such as fillers,e.g. lactose, sucrose, mannitol, maize starch, preferably lactose;lubricants e.g. stearic acid, magnesium stearate, talc or silica ormixtures thereof; preferably a mixture of magnesium stearate, talc andcolloidal silicon dioxide (Aerosil®). Also other pharmaceuticallyacceptable additives such as colorants or flavorings and the like may bepresent.

The “retard” effect or “extended release” effect is due to the fact thatthe cisapride-(L)-tartrate is embedded in a mixture of two viscouspolymers. Hence, the formulation comprises a mixture of a highly viscoushydrophilic polymer and a viscous hydrophilic polymer, which releasesthe active ingredient gradually from the formulation. For the presentactive ingredient, cisapride-(L)-tartrate, this can conveniently beachieved using a mixture of hydroxypropyl methylcellulose and anotherviscous cellulose derivative such as, hydroxypropylcellulose,ethylcellulose, hydroxyethylcellulose, hydroxyethyl methylcellulose,methylcellulose, preferably hydroxypropylcellulose.

These two hydrophilic polymers swell when in contact with water, thuscreating a porous matrix from which the cisapride can gradually bereleased. The said polymers themselves also dissolve slowly in theaqueous medium. Consequently, the surface of the formulation is alsoconstantly dissolving and so the aqueous medium can reach the moreinward mixture of polymers, that in turn begins swelling and releasingactive ingredient thus providing for a continuous release of activeingredient following a zero order to first order kinetics.

The hydroxypropyl methylcellulose used in the above mentioned mixturepreferably has a viscosity of about 15,000 mPa.s, e.g. hypromellose2208.

The hydroxypropylcellulose used in the above mentioned mixture shouldpreferably have a viscosity ranging from 150 to 700 mPas, preferablyfrom 200 to 600 mPa.s, e.g. Klucel EF®.

The relative amount of said mixture of viscous hydrophilic cellulosepolymers in a formulation ranges preferably between 15% and 35% of thetotal composition weight The relative amount of mixture of viscoushydrophilic cellulose polymers correlates with the period during whichthe active ingredient is released. The lowest limit, i.e. 15%, gives areasonably extended release period of about 900 minutes. The highestlimit, i.e. 35% leads to longer release periods yet still releasing allof the active ingredient present in the formulation. At relative amountshigher than 35% there is expected to be an incomplete release of theactive ingredient.

The ratio of the weight hydroxypropyl methylcellulose over weight of theother cellulose polymer ranges from 0.33 to 3. In particular the ratioof the weight of hydroxypropyl methylcellulose over the weighthydroxypropyl cellulose ranges from 0.33 to 3. The preferred ratio is 1,i.e. equal amounts of hydroxypropyl methyl cellulose andhydroxypropylcellulose are present.

The preferred oral formulation of the present invention is a tablet.

Said tablets may have different kinds of shapes, e.g. oblong or rightcircular. The shape of the tablet influences the release period, becauseof the fact that different shapes have a different ratio of surface overvolume.

A person skilled in the art will appreciate that the volume of thetablet is function of other parameters such as, the actual composition,shape, intended period of release and the intended dose. The exemplifiedcompositions are given for right circular tablets with a diameter ofabout 11.5 mm diameter and a height of about 5.2 mm.

Said tablets may have lines or break-marks and may bear a symbol orother markings.

Said tablets can optionally be coated with art-known coatingcompositions. Coated tablets are the preferred formulation in thisinvention. The above ingredients and ratios apply for the“formulation-core” in general, the “tablet-core” in particular. thecompositions of these “formulation-cores” willed be calledcore-compositions hereinafter.

Suitable coating formulations comprise a filmforming polymer such as,for example, hydroxypropyl methylcellulose, e.g. hypromellose 2910 (5mPa.s); a plasticizer such as, for example, a glycol, e.g. propyleneglycol; an opacifier, such as titanium dioxide; a film smoothener, suchas talc. Water is added as a solvent.

Suitable core compositions are:

cisapride-(L)-tartrate: from 2 to 15% by weight filler: from 50 to 70%by weight hydrophilic polymer mixture: from 15 to 35% by weightlubricants: from 0.5% to 10% by weight

Interesting core compositions are:

cisapride-(L)-tartrate: from 5 to 15% by weight filler: from 50 to 70%by weight hydrophilic polymer mixture: from 15 to 35% by weightlubricants: from 0.5% to 10% by weight

More interesting core compositions are:

cisapride-(L)-tartrate: from 8 to 12% by weight filler: from 55 to 65%by weight hydrophilic polymer mixture: from 20 to 25% by weightlubricants: from 2.5% to 8% by weight

Particular core compositions are:

cisapride-(L)-tartrate: about 9% by weight filler: about 61% by weighthydrophilic polymer mixture: about 23.5% by weight lubricants: about6.5% by weight

Preferred core compositions are:

cisapride-(L)-tartrate: about 9% by weight lactose: about 61% by weighthydroxypropyl methylcellulose: from 5.5% to 18% (*) hydroxypropylcellulose from 5.5% to 18% (*) lubricants: about 6.5% by weight (*) thetotal amount of cellulose derivatives in weight percent being about23.5%

In view of the gastrointestinal motility stimulating properties ofcisapride, the present invention provides the use of the presentformulation as a medicine, in particular in treating gastrointestinaldisorders.

Experimental Part EXAMPLE 1

To a stirred solution ofcis-4-amino-5-chloro-N-[1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide(4 g) in ethanol (81 ml) was added a solution of[R(R*,R*)]-2,3-dihydroxybutanedioic acid (1.4 g) in ethanol (20 ml) andthe product was allowed to crystallize. It was filtered off and dried,yielding 4.8 g (89%) of(+)-cis-4-amino-5-chloro-N-[1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide[R(R*,R*)]-2,3-dihydroxybutanedioate (1:1), i.e. cisapride-(L)-tatrate.Melting point is 197.1° C. and [α]_(D) ²⁰ is 6.7 (c=0.1% methanol).

EXAMPLE 2

Ingredients for the preparation of 1000 tablets (570 mg) of formulation1:

% of tablet Ingredient amount weight cisapride-(L)-tartrate  52.92 g 9.3% Lactose 346.08 g 60.7% Hydroxypropylmethylcellulose 2208    66 g11.6% Klucel EF ®  67.95 g 11.9% water (*)    60 g isopropanol (*)   140g magnesium stearate  2.85 g  0.5% Aerosil ®   5.7 g  1.0% talc  28.5 g 5.0% (*) these ingredients are not comprised in the final compositionof the tablet.

Preparation:

The above mentioned amounts of cisapride-(L)-tartrate, lactose,hydroxypropylmethyl-cellulose, Klucel EF® were sieved over astainless-steel frame sieve (mesh 0.95 mm) and were mixed in a planetarypowder mixer during 5 minutes. The mixture was wetted with isopropanoland water. The wetted mixture was again sieved over a frame sieve (mesh:1.8 mm). The mixture was dried overnight at a temperature of 45° C. Thedried granulate was sieved over a frame sieve (mesh: 0.95 mm). The driedand sieved granulate was mixed with sieved magnesium stearate, Aerosil®and talc in a planetary powder mixer during 5 minutes.

Preparation of Tablets:

Using the above described mixture 1000 tablets were compressed.

EXAMPLE 3

Ingredients for the preparation of 1000 tablets (tablets of 570 mg) offormulation 2:

% of tablet Ingredient amount weight cisapride-(L)-tartrate  52.92 g 9.3% lactose 346.08 g 60.7% Hypromellose 2208    40 g  7.0% Klucel EF ® 93.95 g 16.5% water (*)    45 g isopropanol (*)   105 g magnesiumstearate  2.85 g  0.5% Aerosil ®   5.7 g  1.0% talc  28.5 g  5.0% (*)these ingredients are not comprised in the final composition of thetablet.

Preparation is completely analogous to the preparation as described forformulation 1.

EXAMPLE 4

Ingredients for the preparation of 1000 tablets of formulation

cisapride-(L)-tartrate  52.92 mg lactose monohydrate 346.08 mgHypromellose 2208 15000 mPa · s    66 mg Hydroxypropylcellulose  67.95mg water (*) isopropanol (*) magnesium stearate  2.85 mg Aerosil ®   5.7mg Talc  28.5 mg

Coating composition

Hypromellose 2910 5 mPa · s  12 mg propylene glycol  3 mg titaniumdioxide  3 mg talc  2 mg water (*) 120 mg

Preparation

Cisapride-(L)-tartrate, lactose, Hypromellose and Klucel® are mixed in ahigh shear mixture-granulator and wetted with a mixture of isopropanoland water. The granulate thus formed is dried by heating in vacuo. Aftercalibrating the dried granulate aerosil, talc and magnesium stearate areadded and mixed till a homogeneous mixture is obtained Biconvex tabletswith a diameter of 115 mm weighing about 570 mg are compressed.

The tablets are coated in a suitable coating vessel with a coatingsuspension consisting of hypromellose (5 mPa.s), propyleneglycoltitanium dioxide, talc and water.

What is claimed is:
 1. An extended release formulation comprisingcisapride-(L)-tartrate and a mixture of hydroxypropylmethyl celluloseand another viscous polymer, suitable for oral administration.
 2. Anextended release formulation as claimed in claim 1 comprising a mixtureof hydroxypropyl methylcellulose and hydroxypropyl cellulose.
 3. Anextended release formulation as claimed in claim 1 wherein the core ofthe formulation comprises from 15% to 35% of the mixture ofhydroxypropyl methylcellulose and another viscous cellulose polymer. 4.An extended release formulation as claimed in claim 3 wherein the ratioof the weight of hydroxypropyl methylcellulose over the weight ofhydroxypropylcellulose ranges from about 0.33 to about
 3. 5. An extendedrelease formulation as claimed in claim 4 wherein the ratio of theweight of hydroxypropyl methycellulose over the weight ofhydroxypropylcellulose is about
 1. 6. An extended release formulation asclaimed in claim 1 comprising: cisapride-(L)-tartrate: about 9% byweight lactose: about 61% by weight hydroxypropyl methylcellulose: from5.5% to 18% hydroxypropyl cellulose from 5.5% to 18% lubricants: about6.5% by weight,

the total weight percent of cellulose derivatives being about 23.5%. 7.A method of treating gastro-intestinal disorders in patients in need ofthe same, which comprises administering to such patients an effectiveamount of a composition as claimed in any one of claims 1 to 6.